The present proposal extends our multidisciplinary studies of nonopiate analgesia systems. The long term aim is to better understand the behavioral, neurophysiological, anatomical, and pharmacological bases of pain inhibition produced by focal electrical stimulation of specific brainstem areas (midbrain periaqueductal gray=PAG and lateral reticular formation=LRF; hypothalamus; medullary nucleus raphe magnus=NRM and adjacent reticular formation=MRF). This understanding should lead to more effective and innovative means of clinical pain alleviation. Specific goals are: (A) To utilize behavioral methods in rats (tail-flick reflex latency) to assess the presence or absence of analgesia (stimulation-produced analgesia=SPA) and other behavioral reactions evoked by stimulation in PAG, LRF, hypothalamus, MRF, NRM and other sites. (B) To use electrophysiological single-unit microelectrode recording methods to investigate associated inhibitory (or other) effects on noxious heat-evoked responses of single lumbar spinal cord neurons produced by brain stimulation that either did or did not elicit SPA in the same animals (anesthetized with sodium pentobarbital). (C) To develop a new behavioral methodology enabling a quantitative analysis of brainstem modulation of nociceptive behavior (hindlimb flexion withdrawal reflex) for comparison with spinal reflexes and single spinal neuronal activity elicited by identical noxious thermal hindfoot stimulation. This method derives from our earlier work showing that noxious heating of the anesthetized rat's hindfoot elicits hindlimb flexor EMG activity and withdrawal force which are graded with stimulus temperature and which are suppressed by PAG or LRF stimulation. We will study effects of brain stimulation on hindlimb flexor EMG activity and tension (recorded with a miniature strain gauge implanted in tendon of the biceps femoris muscle) elicited by mild, escapable noxious heat stimuli applied to the ventral hindpaw of awake rats. (D) To investigate the pharmacology of SPA and descending inhibitionof spinal neurons, with particular emphasis on monoaminergic, cholinergic, and peptidergic (cholecystokinin, vasopressin) involvement at spinal or supraspinal sites. (E) To investigate the intraspinal and brainstem trajectories of anatomical pathways mediating SPA and descending inhibition of spinal neurons.